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Updated: Sep 27, 2026
Mouse In Vivo Placental Targeted CRISPR Manipulation
Published on: April 14, 2023
Inactivation of the nuclear receptor coactivator RAP250 in mice results in placental vascular dysfunction
Per Antonson1, Gertrud U Schuster, Ling Wang
1Department of Biosciences at Novum, Karolinska Institutet, Novum, S-14157 Huddinge, Sweden. per.antonson@cbt.si.se
Abstract:
Coactivators constitute a diverse group of proteins that are essential for optimal transcriptional activity of nuclear receptors. In the past few years many coactivators have been identified but it is still unclear whether these proteins interact indiscriminately with all nuclear receptors and whether there is some redundancy in their functions. We have previously cloned and characterized RAP250 (ASC-2/PRIP/TRBP/NRC), an LXXLL-containing coactivator for nuclear receptors. In order to study its biological role, Rap250 null mice were generated by gene targeting. Here we show that genetic disruption of Rap250 results in embryonic lethality at embryonic day (E) 13.5. Histological examination of placentas revealed a dramatically reduced spongiotrophoblast layer, a collapse of blood vessels in the region bordering the spongiotrophoblast, and labyrinthine layers in placentas from Rap250(-/-) embryos. These findings suggest that the lethality of Rap250(-/-) embryos is the result of obstructed placental blood circulation. Moreover, the transcriptional activity of PPAR gamma is reduced in fibroblasts derived from Rap250(-/-) embryos, suggesting that RAP250 is an essential coactivator for this nuclear receptor in the placenta. Our results demonstrate that RAP250 is necessary for placental development and thus essential for embryonic development.
Insights
Genetic disruption of the nuclear receptor coactivator RAP250 causes embryonic lethality due to placental defects. This highlights RAP250
Area of Science:
- Molecular Biology
- Developmental Biology
- Genetics
Background:
- Nuclear receptors require coactivators for transcriptional activity.
- RAP250 (also known as ASC-2/PRIP/TRBP/NRC) is an identified coactivator containing an LXXLL motif.
- The precise biological functions and necessity of RAP250 remain to be fully elucidated.
Purpose of the Study:
- To investigate the biological role of RAP250 by generating and analyzing Rap250 null mice.
- To determine the impact of RAP250 deficiency on embryonic and placental development.
- To assess the role of RAP250 in the transcriptional activity of nuclear receptors, specifically PPAR gamma.
Main Methods:
- Gene targeting was employed to create Rap250 null mice.
- Embryonic lethality was assessed at embryonic day 13.5.
- Histological examination of placentas was performed to identify developmental abnormalities.
- Transcriptional activity of PPAR gamma was measured in fibroblasts derived from Rap250(-/-) embryos.
Main Results:
- Rap250 null mice exhibited embryonic lethality at embryonic day 13.5.
- Placentas from Rap250(-/-) embryos showed a reduced spongiotrophoblast layer and collapsed blood vessels.
- Transcriptional activity of PPAR gamma was diminished in Rap250(-/-) fibroblasts.
- These placental defects suggest obstructed blood circulation as the cause of embryonic lethality.
Conclusions:
- RAP250 is essential for normal placental development.
- The absence of RAP250 leads to embryonic lethality, likely due to placental vascular complications.
- RAP250 plays a crucial role as a coactivator for nuclear receptors like PPAR gamma in placental function.
- RAP250 is indispensable for both placental and overall embryonic development.
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